LIPIDS, LIPOPROTEINS

LIPIDS, LIPOPROTEINS

1. LIPIDS

   • major lipids circulating in human blood
     • cholesterol
       • Second largest component of serum lipids
         • Transported in two forms
           • Free cholesterol
             • Mildly polar due to the (OH) group
           • Cholesterol esters
             • non-polar
             • Formed by the action of lecithin-cholesterol acyltransferase (LCAT) enzyme
     • fatty acids
       • Consists of a straight chain of an even number of carbon atoms, with hydrogen atoms along the length of the chain with one methyl group at one end of the chain and a carboxyl group (―COOH) at the other end
       • hydrocarbon chain that can vary in length from two to more than 26 carbons.
       • Classified according with
         • Saturation grade
           • Saturated
             • for instance palmitic acid (16:0=
           • unsaturated
             • mono (one double bond)
               • For instance: Oleic acid or cis,9-octadenoic acid
             • poly (two or more double bonds)
               • For instance Linolenic acid (9-12, octadecadeinoic acid
         • chain lenght
           • Short: C4-C6
           • Medium: C8-C12
           • Large: C14-C22
           • Extra large: >C22
         • Spatial configuration isomery
           • Cis
           • Trans
         • Synthesis
           • Essencial FA
             • Must be included in diet
           • Non-essencial FA
         • First double bond position
           • w-3/w-6/w-9
     • triglycerides
       • Represents the largest percentage of serum lipids
       • Are esters composed of three fatty acids and glycerol
       • non-polar fraction are the triglycerides
       • Its hydrophilic portion is due to the glycerol
     • Phospholipids
       • are fundamental biological building blocks that maintain the proper functioning of plasma and other cellular membranes and are crucial for the survivability of cells and the existence of multicellular life
         • Phospholipids may be synthesized de novo via the Kennedy pathway and salvaged and recycled in a pathway requiring the mitochondria-associated endoplasmic reticulum membrane
         • most common phospholipids
           • Phosphatidic acid (phosphatidate) (PA)
           • Phosphatidylethanolamine (cephalin) (PE)
           • Phosphatidylcholine (lecithin) (PC)
           • Phosphatidylserine (PS)
           • Phosphatidylinositol (PI)
           • Phosphatidylinositol phosphate (PIP)
           • Phosphatidylinositol bisphosphate (PIP2)
           • Phosphatidylinositol trisphosphate (PIP3)
           • Ceramide phosphorylcholine (Sphingomyelin) (SPH)
           • Ceramide phosphorylethanolamine (Sphingomyelin) (Cer-PE)
           • Ceramide phosphoryllipid

2. ENZIMES INVOLVED IN LIPOPROTEIN METABOLISM

   • Hepatic lipase
     • localized to the sinusoidal surface of liver cells
     • mediates the hydrolysis of triglycerides and phospholipids in IDL and LDL leading to smaller particles
     • mediates the hydrolysis of triglycerides and phospholipids in HDL resulting in smaller HDL particles
   • Endothelial lipase
     • This lipase plays a major role in hydrolyzing the phospholipids in HDL
   • Lecithin: cholesterol acyltransferase (LCAT)
     • made in the liver
     • In the plasma, it catalyzes the synthesis of cholesterol esters in HDL by facilitating the transfer of a fatty acid from position 2 of lecithin to cholesterol
   • Cholesteryl ester transfer protein (CETP)
     • synthesized in the liver
     • in the plasma mediates the transfer of cholesterol esters from HDL to VLDL, chylomicrons, and LDL and the transfer of triglycerides from VLDL and chylomicrons to HDL
     • Inhibition of CETP activity leads to an increase in HDL cholesterol and a decrease in LDL cholesterol.
   • Lipoprotein lipase (LPL)
     • is synthesized in muscle, heart, and adipose tissue
       • LPL is strategically located at the dynamic blood-tissue interface (vascular endothelium) from where it can more easily redirect the use of energy-rich substrates, such as FFAs, according to the metabolic demands of the organism.
     • hydrolyzes the triglycerides carried in chylomicrons and VLDL to fatty acids
     • Catabolism of triglycerides results in the conversion of chylomicrons into chylomicron remnants and VLDL into IDL
     • requires Apo C-II as a cofactor
       • Apo A-V also plays a key role in the activation of this enzyme
     • Apo C-III and Apo A-II inhibit the activity of LPL.
     • Insulin stimulates LPL expression and LPL activity is reduced in patients with poorly controlled diabetes, which can impair the metabolism of triglyceride rich lipoproteins leading to hypertriglyceridemia.
     • Regulation of DNA transcription is responsible for the upregulation of LPL gene expression and activity during cardiomyogenesis and adipogenesis
     • Most of the physiological variation in LPL activity (e.g., during exercise and fasting) appears to be driven via posttranslational mechanisms by extracellular proteins
     • LPL activity is also regulated by daily circumstances, such as exercise, fed and fasting states, and starvation and cold, in a very intricate manner
       • LPL plays a crucial physiological role not only in lipoprotein metabolism but also in fuel metabolism.
     • Complex diseases, such as metabolic disorders, require multifarious therapeutic approaches. Nonetheless, some LPL activators (e.g., fibrates) have been proven effective in the treatment of hypertriglyceridemia.

3. LIPOPROTEINS

   • lipids, such as cholesterol and triglycerides, are insoluble in water these lipids must be transported in association with proteins in the circulation.
   • Large quantities of fatty acids from meals must be transported as triglycerides to avoid toxicity.
   • Structure
     • Central hydrophobic core of non-polar lipids
     • hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins
   • Classification
     • Chylomicrons
       • Large triglyceride rich particles made by the intestine
       • involved in the transport of dietary triglycerides and cholesterol to peripheral tissues and liver
       • Density (g/ml)
         • <0.930
       • Size (nm)
         • 75-1200
       • Major Lipids
         • Triglycerides
       • Major Apoproteins
         • Apo B-48, Apo C, Apo E, Apo A-I, A-II, A-IV
       • key enzymes required for triglyceride synthesis are monoacylglycerol acyltransferase (MGAT) and diacylglycerol transferase (DGAT) MGAT catalyzes the addition of a fatty acid to monoacylglycerol while DGAT catalyzes the addition of a fatty acid to diacylglycerol resulting in triglyceride formation
       • The size and composition of the chylomicrons formed in the intestine are dependent on the amount of fat ingested and absorbed by the intestine and the type of fat absorbed
       • Microsomal triglyceride transfer protein (MTP) is required for the movement of lipid from the endoplasmic reticulum to the Apo B-48. The absence of MTP results in the inability to form chylomicrons (Abetalipoproteinemia). Lomitapide inhibits MTP function and is used to treat patients with homozygous Familial Hypercholesterolemia.
     • Chylomicron Remnants
       • Density (g/ml)
         • 0.930- 1.006
       • Size (nm)
         • 30-80
       • Major Lipids
         • Triglycerides -Cholesterol
       • Major Apoproteins
         • Apo B-48, Apo E
       • these particles are enriched in cholesterol and are pro-atherogenic
     • VLDL
       • Density (g/ml)
         • 0.930- 1.006
       • Size (nm)
         • 30-80
       • Major Lipids
         • Triglycerides
       • Major Apoproteins
         • Apo B-100, Apo E, Apo C
           • Apo B-100 is the core structural protein each VLDL contains one Apo B-100 molecule
       • are produced by the liver
     • IDL
       • Size (nm)
         • 25-35
       • Density (g/ml)
         • 1.006- 1.019
       • Major Lipids
         • triglycerides Cholesterol
       • Major Apoproteins
         • Apo B-100, Apo E, Apo C
       • The removal of triglycerides from VLDL by muscle and adipose tissue results in the formation of IDL particles which are enriched in cholesterol
     • HDL
       • Size (nm
         • 5- 12
       • Major Lipids
         • Cholesterol Phospholipids
       • Major Apoproteins
         • Apo A-I, Apo A-II, Apo C, Apo E
           • Apo A-I is the core structural protein and each HDL particle may contain multiple Apo A-I molecules
       • Density (g/ml)
         • 1.063- 1.210
       • important role in reverse cholesterol transport from peripheral tissues to the liver
         • HDL particles have antioxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic properties
       • can be classified based on density, size, charge, or apolipoprotein composition
         • Density gradient ultracentrifugation
           • HDL , HDL , Very high density HDL
         • Gradient gel electrophoresis
           • HDL 2a, 2b, 3a, 3b, 3c
         • Nuclear magnetic resonance
           • large, medium, and small
         • 2-dimensional gel electrophoresis
           • pre-beta 1 and 2, alpha 1, 2, 3, 4
         • Apolipoprotein composition
           • A-I particles, A-I: A-II particles, A-I: E particles
     • LDL
       • Density (g/ml)
         • 1.019- 1.063
       • Size (nm
         • 18- 25
       • Major Lipids
         • Cholesterol
       • Major Apoproteins
         • Apo B-100
       • carries the majority of the cholesterol that is in the circulation
         • metabolism
           • The levels of plasma LDL are determined by the rate of LDL production and the rate of LDL clearance, both of which are regulated by the number of LDL receptors in the liver
           • LDL clearance, approximately 70% of circulating LDL is cleared via hepatocyte LDL receptor mediated endocytosis with the remainder taken up by extrahepatic tissues
           • The levels of LDL receptors in the liver are mainly regulated by the cholesterol content of the hepatocyte
       • considered to be more pro-atherogenic than large LDL
         • have a decreased affinity for the LDL receptor resulting in a prolonged retention time in the circulation
         • easily enter the arterial wall and bind more avidly to intra-arterial proteoglycans, which traps them in the arterial wall
         • are more susceptible to oxidation, which could result in an enhanced uptake by macrophages
     • Lp (a)
       • article that has apolipoprotein (a) attached to Apo B-100 via a disulfide bond. This particle is pro-atherogenic.

4. APOLIPOPROTEINS

   • acts as ligands for lipoprotein receptors
   • serve as activators or inhibitors of enzymes involved in the metabolism of lipoproteins
   • serviing structural role
   • guide the formation of lipoproteins
   • classification
     • Apo B-48
       • Source
         • Intestine
       • Association
         • Chylomicrons
       • Function
         • Structural protein for chylomicrons
     • Apo A-II
       • Source
         • Liver
       • Association
         • HDL, chylomicrons
       • Function
         • Structural protein for HDL, Activates hepatic lipase
     • Apo A-IV
       • Source
         • Intestine
       • Association
         • HDL, chylomicrons
       • Function
         • Unknown
     • Apo A-V
       • Source
         • Liver
       • Association
         • LDL, chylomicrons, HDL
       • Function
         • Promotes LPL mediated TG lipolysis
     • Apo B-100
       • Source
         • Liver
       • Association
         • VLDL, IDL, LDL, Lp (a)
       • Function
         • Structural protein, Ligand for LDL receptor
     • Apo C-I
       • Source
         • Liver
       • Association
         • Chylomicrons, VLDL, HDL
       • Function
         • Activates LCAT
     • Apo C-II
       • Source
         • Liver
       • Association
         • Chylomicrons, VLDL, HDL
       • Function
         • Co-factor for LPL
     • Apo C-III
       • Source
         • Liver
       • Association
         • Chylomicrons, VLDL, HDL
       • Function
         • Inhibits LPL and uptake of lipoproteins
     • Apo A-I
       • Source
         • Liver, Intestine
       • Function
         • Structural protein for HDL, Activates LCAT
       • Association
         • HDL, chylomicrons
     • Apo E
       • Source
         • Liver
       • Association
         • Chylomicron remnants, IDL, HDL
       • Function
         • Ligand for LDL receptor
     • Apo (a)
       • Source
         • Liver
       • Association
         • Lp (a)
       • Function
         • Inhibits plasminogen activation

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